Review Article

The Reasons for Higher Mortality Rate in Opium Addicted Patients with COVID-19: A Narrative Review


The outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused COVID-19 has developed into an unexampled worldwide pandemic. The most important cause of death in patients with COVID-19 is Acute Respiratory Distress Syndrome (ARDS). Opium is widely used for its analgesic features in control of acute and chronic pain related to different diseases. Opium consumption is increased over the last three decades and leads to adverse effects on the respiratory system; opium also affects the lungs' functions and respiration. The contemplative issue is the higher mortality rate due to SARS-CoV-2 infection in opium addicts’ patients. Studies have shown that despite the decrease in proinflammatory cytokines production in opium addicts, there are at least 4 reasons for this increase in mortality rate: downregulation of IFNs expression, development of pulmonary edema, increase thrombotic factors, increase the expression of Angiotensin-converting enzyme 2 (ACE2). Therefore, identifying the causes of mortality and approved therapies for the treatment of COVID-19 patients who use opium for any reason is an important unmet need to reduce SARS-CoV-2 infection-related mortality. This review study demonstrated the effects of opium on immune responses and the reasons for the higher mortality rate in opium addicts’ patients with COVID-19.

1. Kelvin DJ, Rubino S (2020). Fear of the novel coronavirus. J Infect Dev Ctries, 14(1):1-2.
2. Romagnoli S, Peris A, De Gaudio AR, Geppetti P (2020). SARS-CoV-2 and COVID-19: From the Bench to the Bedside. Physiol Rev, 100(4):1455-1466.
3. Li X, Geng M, Peng Y, et al (2020). Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal,10(2):102-108.
4. Mantlo E, Bukreyeva N, Maruyama J, et al (2020). Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res,179:104811.
5. Algera MH, Kamp J, van der Schrier R, et al (2019). Opioid-induced respiratory depression in humans: a review of pharmacokinetic–pharmacodynamic modelling of reversal. Br J Anaesth, 122(6):e168-e179.
6. Al-Hashimi M, Scott S, Thompson J, Lambert D (2013). Opioids and immune modulation: more questions than answers. Br J Anaesth, 111(1):80-88.
7. Plein LM, Rittner HL (2018). Opioids and the immune system–friend or foe. Br J Pharmacol, 175(14):2717-2725.
8. Ataei M, Shirazi FM, Lamarine RJ, et al (2020). A double-edged sword of using opioids and COVID-19: a toxicological view. Substance Abuse Treatment, Prevention, and Policy, 15:1-4.
9. Armario A (2010). Activation of the hypothalamic–pituitary–adrenal axis by addictive drugs: different pathways, common outcome. Trends Pharmacol Sci, 31(7):318-25.
10. Wei Y, Shah R (2020). Substance use disorder in the COVID-19 pandemic: a systematic review of vulnerabilities and complications. Pharmaceuticals (Basel), 13(7):155.
11. Sajja RK, Rahman S, Cucullo L (2016). Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress. J Cereb Blood Flow Metab, 36(3):539-54.
12. Holden JE, Jeong Y, Forrest JM (2005). The endogenous opioid system and clinical pain management. AACN Clin Issues, 16(3):291-301.
13. Trigo JM, Martin-García E, Berrendero F, et al (2010). The endogenous opioid system: a common substrate in drug addiction. Drug Alcohol Depend, 108(3):183-94.
14. Ocasio FM, Jiang Y, House SD, Chang SL (2004). Chronic morphine accelerates the progression of lipopolysaccharide-induced sepsis to septic shock. J Neuroimmunol, 149(1-2):90-100.
15. Saeedi M O-NV, Maleki I, Hedayatizadeh-Omran A, et al (2020). Opium Addiction and COVID-19: Truth or False Beliefs. ranian Journal of Psychiatry and Behavioral, 14 (2); e103509.
16. Wang QQ, Kaelber DC, Xu R, Volkow ND (2020). COVID-19 risk and outcomes in patients with substance use disorders: analyses from electronic health records in the United States. Molecular Psychiatry, 30–39.
17. Weid M, Ziegler J, Kutchan TM (2004). The roles of latex and the vascular bundle in morphine biosynthesis in the opium poppy, Papaver somniferum. Proc Natl Acad Sci U S A, 101(38):13957-62.
18. Heydari M, Hashem Hashempur M, Zargaran A (2013). Medicinal aspects of opium as described in Avicenna’s Canon of Medicine. Acta Med Hist Adriat, 11(1):101-12.
19. Facchini PJ, Park S-U (2003). Developmental and inducible accumulation of gene transcripts involved in alkaloid biosynthesis in opium poppy. Phytochemistry, 64(1):177-86.
20. Arora PK, Fride E, Petitto J, et al (1990). Morphine-induced immune alterations in vivo. Cell Immunol, 126(2):343-53.
21. Mirzaeipour F, Azdaki N, Mohammadi G, Addasi E (2013). The effects of opium addiction through different administration routes on inflammatory and coagulation factors. ournal of Kerman University of Medical Sciences, 20:292-300.
22. Azarang A, Mahmoodi M, Rajabalian S, et al (2007). T-helper 1 and 2 serum cytokine assay in chronic opioid addicts. Eur Cytokine Netw, 18(4):210-4.
23. Steffens C, Sung M, Bastian LA, et al (2020). The association between prescribed opioid receipt and community-acquired pneumonia in adults: a systematic review and meta-analysis. J Gen Intern Med, 35(11)3315:3322.
24. Nabati S, Asadikaram G, Arababadi MK, et al (2013). The plasma levels of the cytokines in opium-addicts and the effects of opium on the cytokines secretion by their lymphocytes. Immunol Lett, 152(1):42-6.
25. Wang J, Barke RA, Ma J, et al (2008). Opiate abuse, innate immunity, and bacterial infectious diseases. Arch Immunol Ther Exp (Warsz), 56(5):299-309.
26. Eisenstein TK, Kaminsky DE, Rahim RT, Rogers TJ (2008). Drugs of abuse and the immune system. Neuroimmune Pharmacology, 531-543.
27. Welters I, Menzebach A, Goumon Y, Langefeld T, et al (2000). Morphine suppresses complement receptor expression, phagocytosis, and respiratory burst in neutrophils by a nitric oxide and μ3 opiate receptor-dependent mechanism. J Neuroimmunol, 111(1-2):139-45.
28. Bosshart H (2010). Morphine-mediated suppression of phagocytosis. Int Immunopharmacol, 10(2):264-5.
29. Shahrani M, Rafieian-Kopaei M (2009). Comparison of morphine and tramadol effects on phagocytic activity of mice peritoneal phagocytes in vivo. Int Immunopharmacol, 9(7-8):968-70.
30. Delgado-Vélez M, Lugo-Chinchilla A, Lizardo L, et al (2008). Chronic exposure of human macrophages in vitro to morphine and methadone induces a putative tolerant/dependent state. J Neuroimmunol, 196(1-2):94-100.
31. Frenklakh L, Bhat RS, Bhaskaran M, et al (2006). Morphine-Induced Degradation of the Host Defense Barrier. Digestive Diseases and Sciences, 51:318-325.
32. Chang M-C, Fan S-Z, Hsiao P-N, et al (2011). Influence of morphine on host immunity. Acta Anaesthesiol Taiwan, 49(3):105-8.
33. Madera-Salcedo IK, Cruz SL, Gonzalez-Espinosa C (2011). Morphine decreases early peritoneal innate immunity responses in Swiss–Webster and C57BL6/J mice through the inhibition of mast cell TNF-α release. J Neuroimmunol, 232(1-2):101-7.
34. Wang J, Barke RA, Charboneau R, Roy S (2005). Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection. J Immunol, 174(1):426-34.
35. Eisenstein TK (2019). The Role of Opioid Receptors in Immune System Function. Front Immunol, 10:2904.
36. Greeneltch KM, Kelly-Welch AE, Shi Y, Keegan AD (2005). Chronic morphine treatment promotes specific Th2 cytokine production by murine T cells in vitro via a Fas/Fas ligand-dependent mechanism. J Immunol, 175(8):4999-5005.
37. Guo S-L, Lin C-J, Huang H-H, et al (2006). Reversal of morphine with naloxone precipitates haloperidol-induced extrapyramidal side effects. J Pain Symptom Manage, 31(5):391-2.
38. Min TJ, Kim J-i, Kim J-H, et al (2011). Morphine postconditioning attenuates ICAM-1 expression on endothelial cells. J Korean Med Sci, 26(2):290-6.
39. Schneider MA, Meingassner JG, Lipp M, et al (2007). CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J Exp Med, 204(4): 735–745.
40. Williams IR (2006). CCR6 and CCL20: partners in intestinal immunity and lymphorganogenesis. Ann N Y Acad Sci, 1072:52-61.
41. Dunne JL, Collins RG, Beaudet AL, et al (2003). Mac-1, but not LFA-1, uses intercellular adhesion molecule-1 to mediate slow leukocyte rolling in TNF-α-induced inflammation. J Immunol, 171(11):6105-11.
42. Rogers TJ (2020). Bidirectional Regulation of Opioid and Chemokine Function. Front Immunol, 11:94.
43. Homan JW, Steele AD, Martinand-Mari C, et al (2002). Inhibition of morphine-potentiated HIV-1 replication in peripheral blood mononuclear cells with the nuclease-resistant 2-5A agonist analog, 2-5AN6B. J Acquir Immune Defic Syndr, 30(1):9-20.
44. Miyagi T, Chuang LF, Lam KM, et al (2000). Opioids suppress chemokine-mediated migration of monkey neutrophils and monocytes—an instant response. Immunopharmacology, 47(1):53-62.
45. Sun W, Chang M, Hsiao P, et al (2010). Morphine-sparing effect by COX-1 inhibitor sustains analgesic function without compromising antigen-specific immunity and antitumor effect of naked DNA vaccine. Int J Immunopathol Pharmacol, 23(1):91-104.
46. Cheng W-F, Chen L-K, Chen C-A, et al (2006). Chimeric DNA vaccine reverses morphine-induced immunosuppression and tumorigenesis. Mol Ther, 13(1):203-10.
47. Krantz AJ, Hershow RC, Prachand N, et al (2003). Heroin insufflation as a trigger for patients with life-threatening asthma. Chest, 123(2):510-7.
48. Wang J, Charboneau R, Balasubramanian S, et al (2001). Morphine modulates lymph node‐derived T lymphocyte function: role of caspase‐3,‐8, and nitric oxide. J Leukoc Biol, 70(4):527-536.
49. Börner C, Warnick B, Smida M, et al (2009). Mechanisms of opioid-mediated inhibition of human T cell receptor signaling. J Immunol, 183(2):882-9.
50. Wang J, Barke RA, Charboneau R, et al (2003). Morphine negatively regulates interferon-γ promoter activity in activated murine T cells through two distinct cyclic AMP-dependent pathways. J Biol Chem, 278(39):37622-31.
51. O'garra A, Murphy KM (2009). From IL-10 to IL-12: how pathogens and their products stimulate APCs to induce Th 1 development. Nat Immunol, 10(9):929-32.
52. Sacerdote P, Limiroli E, Gaspani L (2013). Experimental evidence for immunomodulatory effects of opioids. In: Madame Curie Bioscience Database [Internet]. Ed(s): Landes Bioscience.
53. Ghazavi A, Solhi H, Moazzeni SM, et al (2013). Cytokine profiles in long-term smokers of opium (Taryak). J Addict Med, 7(3):200-3.
54. Casalinuovo I, Gaziano R, Francesco PD (2000). Cytokine pattern secretion by murine spleen cells after inactivated Candida albicans immunization. Effect of cocaine and morphine treatment. Immunopharmacol Immunotoxicol, 22(1):35-48.
55. Roy S, Balasubramanian S, Sumandeep S, et al (2001). Morphine directs T cells toward Th2 differentiation. Surgery, 130(2):304-9.
56. Channappanavar R, Fehr AR, Zheng J, et al (2019). IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest, 129(9):3625-3639.
57. Channappanavar R, Fehr AR, Vijay R, et al (2016). Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe, 19(2):181-93.
58. Lazear HM, Schoggins JW, Diamond MS (2019). Shared and distinct functions of type I and type III interferons. Immunity, 50(4):907-923.
59. Stanifer ML, Kee C, Cortese M, et al (2020). Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells. Cell Rep, 32(1):107863.
60. Lokugamage KG, Hage A, Schindewolf C, et al (2020). SARS-CoV-2 is sensitive to type I interferon pretreatment. bioRxiv, doi: 10.1101/2020.03.07.982264.
61. Blanco-Melo D, Nilsson-Payant BE, Liu W-C, et al(2020). Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell, 181(5):1036-1045.
62. O’Brien TR, Thomas DL, Jackson SS, et al (2020). Weak induction of interferon expression by SARS-CoV-2 supports clinical trials of interferon lambda to treat early COVID-19. Clin Infect Dis, 71(6):1410-1412.
63. James N (2017). Fenner's veterinary virology. ed. Elsevier Academic Press.
64. Park WB, Kwon N-J, Choi S-J, et al (2019). Virus isolation from the first patient with SARS-CoV-2 in Korea. J Korean Med Sci, 35(7):e84.
65. Zhang H, Zhou P, Wei Y, et al (2020). Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19. Ann Intern Med, 172(9):629-632.
66. Chen I-Y, Moriyama M, Chang M-F, Ichinohe T (2019). Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol, 10:50.
67. Wang J, Charboneau R, Balasubramanian S, et al (2002). The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the μ‐opioid receptor. J Leukoc Biol, 71(5):782-90.
68. Alexander GC, Stoller KB, Haffajee RL, Saloner B (2020). An epidemic in the midst of a pandemic: opioid use disorder and COVID-19. Ann Intern Med, 2 : M20-1141.
69. Becker WC, Fiellin DA (2020). When epidemics collide: coronavirus disease 2019 (COVID-19) and the opioid crisis. Ann Intern Med, 173(1):59-60.
70. Yamanaka T, Sadikot RT (2013). Opioid effect on lungs. Respirology, 18(2):255-62.
71. Kumar K, Holden WE (1986). Drug-induced pulmonary vascular disease—mechanisms and clinical patterns. West J Med, 145(3):343-9.
72. Tomashefski Jr JF (2000). Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med, 21(3):435-66.
73. Hsiao P-N, Chang M-C, Cheng W-F, et al (2009). Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways. Toxicology, 256(1-2):83-91.
74. Liu H-C, Anday JK, House SD, Chang SL (2004). Dual effects of morphine on permeability and apoptosis of vascular endothelial cells: morphine potentiates lipopolysaccharide-induced permeability and apoptosis of vascular endothelial cells. J Neuroimmunol, 146(1-2):13-21.
75. Krajnik M, Schäfer M, Sobański P, et al (2010). Local pulmonary opioid network in patients with lung cancer: a putative modulator of respiratory function. Pharmacol Rep, 62(1):139-49.
76. Sacerdote P (2008). Opioid-induced immunosuppression. Curr Opin Support Palliat Care, 2(1):14-8.
77. Nakhaee S, Ghasemi S, Karimzadeh K, et al (2020). The effects of opium on the cardiovascular system: a review of side effects, uses, and potential mechanisms. Subst Abuse Treat Prev Policy, 15(1):30.
78. Michán S, Li Y, Chou MM-H, et al (2010). SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci, 30(29):9695-707.
79. Clarke NE, Belyaev ND, Lambert DW, Turner AJ (2014). Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress. Clin Sci (Lond), 126(7):507-16.
80. Ferguson D, Koo JW, Feng J, et al (2013). Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action. J Neurosci, 33(41):16088-98.
81. Cai H (2020). Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir Med, 8(4):e20.
82. Volkow ND (2020). Collision of the COVID-19 and Addiction Epidemics. Ann Intern Med, 173(1):61-62.
IssueVol 50 No 3 (2021) QRcode
SectionReview Article(s)
Opium Cytokine storm COVID-19 IFNs

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DOLATI-SOMARIN A, ABD-NIKFARJAM B. The Reasons for Higher Mortality Rate in Opium Addicted Patients with COVID-19: A Narrative Review. Iran J Public Health. 50(3):470-479.